Department of Pharmacology, School of Medicine and Public Health, and Program in Molecular and Cellular Pharmacology, University of Wisconsin-Madison, Madison, Wisconsin, USA.
Cancer Res. 2011 Feb 15;71(4):1282-91. doi: 10.1158/0008-5472.CAN-10-2480. Epub 2011 Feb 8.
Increased β-catenin transcriptional activity downstream of the Wnt/Wingless signaling pathway has been observed in many human tumors, most notably colorectal carcinomas. However, β-catenin activation is also observed in many human malignancies with no observable Wnt activity. Wnt-independent pathways that activate β-catenin remain undefined, yet have the potential to play a significant role during tumorigenesis. Here, we report that phosphotidylinositol phosphate kinase Iγ (PIPKIγ), an enzyme that generates phosphoinositide messengers in vivo, directly associates with β-catenin and increases β-catenin activity downstream of growth factor stimulation. PIPKIγ expression and kinase activity enhance β-catenin phosphorylation on residues that promote nuclear importation and transcriptional activity. Lastly, we show that β-catenin is required for PIPKIγ-dependent increased cell proliferation. These results reveal a novel mechanism in which PIPKIγ expression and catalytic activity enhance β-catenin nuclear translocation and expression of its target genes to promote tumorigenic phenotypes.
在许多人类肿瘤中，尤其是结直肠癌细胞中，已经观察到 Wnt/Wingless 信号通路下游的 β-连环蛋白转录活性增加。然而，在许多没有明显 Wnt 活性的人类恶性肿瘤中也观察到 β-连环蛋白的激活。激活 β-连环蛋白的 Wnt 非依赖性途径尚不清楚，但有可能在肿瘤发生过程中发挥重要作用。在这里，我们报告说，磷酸肌醇磷酸激酶 Iγ（PIPKIγ），一种在体内产生磷酸肌醇信使的酶，直接与 β-连环蛋白结合，并在生长因子刺激后增加 β-连环蛋白的活性。PIPKIγ 的表达和激酶活性增强了 β-连环蛋白在促进核输入和转录活性的残基上的磷酸化。最后，我们表明 β-连环蛋白是 PIPKIγ 依赖性增加细胞增殖所必需的。这些结果揭示了一种新的机制，即 PIPKIγ 的表达和催化活性增强了 β-连环蛋白的核易位和其靶基因的表达，从而促进了致瘤表型。
